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AIDS 2014: COPD Is Common Among People with HIV Even At High CD4 Counts

Chronic obstructive pulmonary disease (COPD) is not uncommon among HIV positive adults with CD4 counts above 500 cells/mm³ -- that is, even fairly early in the course of infection -- according to the first findings from a pulmonary substudy of the large international Strategic Timing of Antiretroviral Treatment (START) trial, presented At the 20th International AIDS Conference last month in Melbourne. Among the nearly 1000 participants with good quality spirometry (pulmonary function) tests, the overall COPD prevalence was 6.8%, but there was considerable variation across regions.

"We also found that this varied by smoking status and age," said Ken Kunisaki of the University of Minnesota, who presented the findings. But despite the higher risk among smokers, more than half of the COPD was diagnosed in people who reported that they had never smoked.

COPD Background

COPD is a progressive lung disorder that makes it difficult to breathe, particularly after exertion, ultimately limiting physical activity. It is characterized by emphysema (disruption of the alveolar-capillary units where blood and air meet in the lung, with destruction of lung tissue), airway inflammation, airway fibrosis, and a decrease in airway recoil or elasticity. This leads to airways that are both collapsible and narrowed. Consequently, air becomes trapped in the lungs and the chest becomes hyper-inflated, particularly with activity, causing people with COPD to suffer from shortness of breath (dyspnea), often with chronic cough and sputum production.

COPD is a rising global health problem and is becoming more common among the general population. In recent years, it has become the third leading cause of death globally -- along with other conditions that HIV is known to exacerbate, such as stroke and ischemic heart disease.

Cigarette smoking is the main risk factor for COPD. Other factors that may also contribute to the risk of COPD include indoor air pollution (particularly in settings where wood is used to cook and heat the home) and alpha-1-antitrypsin deficiency, a genetic condition most common in northern Europeans.

A number of observational studies have reported that HIV is an independent COPD risk factor, even after adjusting for the high prevalence of cigarette smoking among people living with HIV. The mechanism for this is not entirely clear, but it could be due to damage caused by HIV-related lung infections, HIV-related oxidative stress and chronic inflammation, or perhaps even some antiretroviral drugs.

COPD prevalence among people with HIV has varied markedly from study to study, ranging from 3% to 23%. Kunasaki noted that much of the variation could be due to the fact that most of these studies were relatively small single-site studies in different populations living with HIV. (Some of these studies were reported at this year's Retrovirus Conference).

The START Pulmonary Substudy

The rationale for this pulmonary substudy of START was to assess COPD prevalence across large globally representative samples of people with HIV. START -- designed to compare the clinical benefit of initiating antiretroviral treatment immediately versus deferring treatment until CD4 cells fall below 500 cells/mm³ -- provided the perfect context to do this, as the study is being performed at hundreds of sites in dozens of countries and has a targeted enrollment of 4000 participants.

Overall, this pulmonary substudy enrolled 1026 participants from 80 sites in 20 countries. The median age was 36 years and the median duration of known HIV infection was 1.2  years. Overall, 29% were women, however, in Africa, 64% were women. The median CD4 cell count was 648 cells/mm³ and about 10% had undetectable HIV viral load (below 400 copies/mL). 28% were current smokers (significantly more common, reported by 45% in Europe, Israel, and Australia) while 11% were former smokers. This left 61% who said they had never smoked, included the vast majority, 80%, in Africa. HIV transmission category also varied by region; overall, 49% reported acquiring HIV from male-to-male sexual contact, 50% through heterosexual contact, and 1% via injection drug use.

The substudy had to exclude participants under the age of 25 because the investigators are also trying to look at the decline in lung function over time; lung function in people under age 25 may still be maturing and increasing, and could thus skew the results. Other exclusion criteria also included use of asthma medications and contraindications to post-bronchodilator spirometry, such as having unstable heart disease, surgery within the past 6 months, a respiratory illness within 6 weeks, or an allergy to albuterol/salbutamol (asthma medications).

Pulmonary function tests were performed at each site by trained technicians using portable spirometer devices, which have been well validated against more formal spirometry tests. Tests that did not meet quality control criteria were excluded from the cross-sectional analysis.

Pulmonary function tests measure the amount (volume) and speed (flow) of air that can be inhaled and exhaled. The "GOLD" definition of COPD is based on forced expiratory volume in 1 second (FEV1 -- how much air can be exhaled within one second) and forced vital capacity (FVC -- how much can be exhaled overall) after the administration of a bronchodilator.

Most people should be able to exhale most of the air from their lungs within 1 second. People with COPD have a significantly reduced ratio of FEV1 to FVC compared to a healthy person. The formal definition for COPD in this study was FEV1/FVC lower than the 5th percentile of predicted levels, based on what is normal in the region and population.

Results

• COPD was diagnosed in 6.8% of the 966 (out of 1026) participants with high quality spirometry results.
• The percentage diagnosed with COPD varied by region:

o   2% in Asia;

o   9.1% in Europe/Israel/Australia;

o   7.8% in Africa;

o   8.2% in the U.S.;

o   3.3 in Mexico and South America.

• Most COPD was of mild (52.2%) or moderate (43.3%) severity.
• The risk of COPD increased with age, with 9.2% of those over age 44 diagnosed with COPD.
• The risk of COPD was significantly higher among current smokers, at 11.8%.
• A multivariate analysis confirmed that that COPD was associated with older age, increased smoking, and differed by region.
• However, more than half of the participants with COPD diagnoses reported never smoking.

Kunisaki suggested that the high proportion of COPD among people who never smoked may have been due to the high rate of COPD diagnoses in Africa, again, a region where smoking was not as common.

"It's a little hard to know what is driving that," he said, "but I think it could be due to other non-smoking exposures, things like biomass fuel exposures and occupational dust/smoke exposure."

Unfortunately, the researchers have not yet collected data on these factors, but they are in discussions about how to do so as the study moves forward, particularly from sites in resource-limited countries.

Other potential factors that came up during the discussion was a history of tuberculosis -- although active TB was an exclusion criterion -- and the possibility that repeated minor respiratory infections may be more common and cause more damage in some communities. It should be noted that many people living with HIV in some resource-constrained settings are diagnosed with HIV at roughly the same time they are being diagnosed with TB.

Clinical Implications

"The clinical implications would highlight the importance of smoking cessation in people living with HIV especially in relation to the prevention of COPD," Kunisaki said. "Another implication is that as people living with HIV continue to age, we are likely to see more and more COPD emerge, and as a consequence of that, I think it is important to familiarize their care providers with the tools for COPD screening, diagnosis, and management."

The importance of this may be underscored with more longitudinal prospective data from the study. Kunisaki noted that another recent small study in Denmark reported rates of COPD doubling in people living with HIV, going from 9.5% to 19% in as little as 4.4 years. This effect would appear to be too high to just be due solely to an increase in age.

The START substudy will also try to conclusively answer whether ART has a positive or negative effect on lung function, as data to date have been conflicting.

8/7/14

Reference

K Kunisaki, D Niewoehner, G Collins G, et al (INSIGHT START Study Team). Chronic obstructive pulmonary disease (COPD) in a large international cohort of HIV-infected adults with CD4+ >500 cells/mm³. 20th International AIDS Conference. Melbourne, July 20-25 2014. Abstract WEAB0104.